Abstract
Cisplatin (CDDP)-induced nephrotoxicity (CIN) is dose-limiting. We revealed that co-administration of non-steroid anti-inflammatory drugs and baseline comorbidity of diabetes mellitus (DM) are associated with CIN development in the short hydration method; however, the results were accessorily obtained without appropriate power calculation. This study aimed to demonstrate the influence of DM complications on CIN incidence in a real-world setting. Lung cancer patients receiving CDDP (≥ 75 mg/m2)-containing regimens with a short hydration method (n = 227) were retrospectively evaluated. The patients were divided into control and baseline DM complication groups. The primary endpoint was the evaluation of CIN incidence between the groups. Propensity score-matching was performed to confirm the robustness of the primary analysis results. CIN occurred in 6.8% of control and 27.0% of DM patients, respectively, with a significant difference in all-patient populations (P = 0.001). In addition, variation of serum creatinine and creatinine clearance significantly worsened in DM patients. Similar results were obtained in a propensity-matched population. Multivariate logistic regression analysis found that DM complication is a singular risk factor for CIN development (adjusted odds ratio; 4.31, 95% confidence interval; 1.62–11.50, P = 0.003). In conclusion, our study revealed that baseline DM complications significantly worsen CIN.
Subject terms: Oncology, Cancer
Introduction
Chemotherapy is the main treatment strategy for advanced lung cancer1,2, and managing chemotherapy-induced adverse effects is necessary for safe, effective treatment and patient quality of life.
Cisplatin (CDDP) is a key chemotherapeutic agent in treating lung cancer in combination with radiotherapy and surgery1,2. In contrast, it induces nausea, vomiting, hearing impairment, neuropathy, and nephrotoxicity3. CDDP-induced nephrotoxicity (CIN) is dose-relatedly reversible and is known to be its dose-limiting toxicity3. CIN used to occur in 30–40% of the patients3. However, the progress of CIN management, including magnesium supplementation, quality antiemetic therapy, and appropriate diuretics administration, significantly reduced its occurrence to 0–10%3–11.
Many reports evaluate CIN risk factors, although most were conducted using old CDDP administration methods without sufficient CIN prophylaxis described above, suggesting some do not reflect real-world settings12–22. We have revealed that co-administration of non-steroid anti-inflammatory drugs (NSAIDs) and baseline comorbidity of diabetes mellitus (DM) are significantly associated with CIN incidence in the short hydration method, the most advanced CDDP administration method4. However, the results were obtained without sufficient power calculation. The prevalence rate of DM is increasing worldwide, and people with prediabetes are also growing23. Therefore, the CDDP administration to DM patients is increasing. It is important to manage CIN in higher-risk patients although there is a lack of evidence in the population. This study aimed to determine the real-world impact of DM complications on CIN incidence.
Results
Patient characteristics
In total, 227 patients were enrolled in this study based on its eligibility criteria (Fig. 1). The baseline patient characteristics (all-patient population and propensity score-matched population) are shown in Table 1. Patients in the DM group were significantly older and staged earlier than controlled patients. In addition, patients with cardiovascular diseases (controlled hypertension and ischemic heart disease, according to a previous report19) were more included in the DM group than control patients. In contrast, no background differences were confirmed between the groups in the propensity score-matched population. Patients with co-administered NSAIDs, an independent CIN risk factor, accounted for 13.7% of the control group and 13.5% of the DM group in all populations, and 6.1% and 12.1% in propensity-matched populations, respectively, without significant difference. Total administration cycles were not different between the groups (median cycles 4 [interquartile range 2–4 cycles] for both groups in the all-patient population, P = 0.54; 4 cycles [2–4 cycles] for propensity-matched population, P = 0.58). All DM patients were type 2 with well-controlled HbA1c (median 6.6%, range 5.4–9.3%). During the evaluation periods, none of the patients had type 1 DM. Detailed DM medication is shown in Supplemental Table 1.
Figure 1.
Design of this study.
Table 1.
Patient characteristics for all patients and propensity-matched patients.
| All-patient analysis | Propensity-matched analysis | |||||
|---|---|---|---|---|---|---|
| Control group | DM group | P-value | Control group | DM group | P-value | |
| No. of patients | 190 | 37 | 33 | 33 | ||
| Gender: male/female | 125/65 | 28/9 | 0.34 | 26/7 | 24/9 | 0.77 |
| Median age (range) | 63 (32–75) | 66 (46–75) | 0.04* | 64 (38–75) | 66 (46–75) | 0.70 |
| Performance status | ||||||
| 0–1/2 | 183/7 | 35/2 | 0.64 | 33/0 | 32/1 | 1.00 |
| BSA (m2) (median, range) | 1.66 (1.28–2.00) | 1.73 (1.36–2.02) | 0.12 | 1.68 (1.41–1.97) | 1.72 (1.36–2.02) | 0.69 |
| Staging | ||||||
| Stage IV, Recurrence/Others | 85/105 | 10/27 | 0.048* | 12/21 | 10/23 | 0.79 |
| Adjuvant chemotherapy (n, %) | 46 (24.2) | 9 (24.3) | 1.00 | 8 (24.2) | 9 (27.3) | 1.00 |
| Treatment line | ||||||
| First line/Second or later line | 26/164 | 4/33 | 0.79 | 3/30 | 4/29 | 1.00 |
| Albumin (g/dL) (median, range) | 4.0 (1.4–4.9) | 4.0 (2.3–4.8) | 0.43 | 4.1 (2.6–4.6) | 4.0 (2.3–4.8) | 0.89 |
| Hemoglobin (g/dL) (median, range) | 12.9 (7.7–16.7) | 13.0 (10.3–15.6) | 0.34 | 13.0 (10.5–16.0) | 13.2 (10.3–15.6) | 0.97 |
| Creatinine (mg/dL) (median, range) | 0.68 (0.35–1.08) | 0.69 (0.40–1.03) | 0.42 | 0.72 (0.40–1.08) | 0.69 (0.40–1.03) | 0.91 |
| CCr (mL/min) (median, range) | 95.8 (51.5–165.1) | 95.7 (61.3–136.9) | 0.96 | 89.6 (51.5–155.0) | 95.7 (61.3–136.9) | 0.51 |
| eGFR (mL/min/1.73 m2) (median, range) | 78.4 (49.9–140.5) | 80.4 (53.5–120.2) | 0.93 | 79.7 (49.9–119.8) | 80.4 (53.5–120.2) | 0.91 |
| Sodium (mEq/L) (median, range) | 140 (125–144) | 139 (133–144) | 0.36 | 139 (125–144) | 140 (133–144) | 0.78 |
| Potassium (mEq/L) (median, range) | 4.2 (3.3–5.0) | 4.2 (3.1–5.1) | 1.00 | 4.3 (3.8–4.9) | 4.2 (3.1–5.1) | 0.25 |
| Chloride (mEq/L) (median, range) | 104 (92–109) | 104 (94–109) | 0.34 | 104 (92–109) | 104 (94–109) | 0.61 |
| Co-administration of NSAIDs (n, %) | 26 (13.7) | 5 (13.5) | 1.00 | 2 (6.1) | 4 (12.1) | 0.67 |
| Co-administration of PPI (n, %) | 84 (44.2) | 18 (48.6) | 0.72 | 18 (54.5) | 15 (45.5) | 0.62 |
| Cardiovascular diseases (n, %) | 48 (25.3) | 20 (54.1) | 0.001** | 16 (48.5) | 16 (48.5) | 1.00 |
| Chemotherapy regimen (n, %) | ||||||
| CDDP + PEM | 51 (26.8) | 7 (18.9) | 6 (18.2) | 7 (21.2) | ||
| CDDP + PEM + BV | 30 (15.8) | 1 (2.7) | 4 (12.1) | 1 (3.0) | ||
| CDDP + VNR | 74 (39.0) | 16 (43.2) | 13 (39.4) | 12 (36.4) | ||
| CDDP + ETP | 35 (18.4) | 13 (35.1) | – | 10 (30.3) | 13 (39.4) | |
*P < 0.05; **P < 0.01.
DM diabetes mellitus, BSA body surface area, CCr creatinine clearance, eGFR estimated glomerular filtration rate, NSAIDs non-steroid anti-inflammatory drugs, PPI proton pump inhibitors, CDDP cisplatin, PEM pemetrexed, BV bevacizumab, VNR vinorelbine, ETP etoposide.
Comparison of CIN incidence and variation of serum creatinine levels and creatinine clearance
CIN occurred in 6.8% of control and 27.0% of DM patients, respectively, with a significant difference in the all-patient population, meeting the study's primary endpoint (Fig. 2A). In addition, variation of serum creatinine (SCr) levels and creatinine clearance (CCr) significantly worsened in DM patients (Fig. 2A,B). Similar results were also obtained in propensity-matched populations, with significant differences (Fig. 2C,D).
Figure 2.
Comparison of (A) CIN incidence and SCr variation and (B) CCr variation in all-patient population, and (C) CIN incidence and SCr variation and (D) CCr variation in propensity-matched population. CIN, cisplatin-induced nephrotoxicity.
Incidence and severity of gastrointestinal symptoms and hearing impairment
Management of chemotherapy-induced nausea and vomiting (CINV) according to current guidelines24 is important for sufficient oral hydration, which is an important hydration method. Therefore, in addition to hearing impairment, we also evaluated nausea, vomiting, and anorexia (Table 2). The incidence and severity of gastrointestinal adverse effects and hearing impairment were similar in both populations.
Table 2.
Incidence and severity of nausea, vomiting, anorexia, and hearing impairment in all subsequent cycles.
| All-patient analysis | Propensity-matched analysis | |||||
|---|---|---|---|---|---|---|
| Control group (n = 190) | DM group (n = 37) | P-value | Control group (n = 33) | DM group (n = 33) | P-value | |
| Nausea | ||||||
| All grade | 121 (63.7%) | 18 (48.7%) | 0.10 | 17 (51.5%) | 16 (48.5%) | 1.00 |
| Grade 1 | 55 (28.9%) | 7 (18.9%) | 7 (21.2%) | 7 (21.2%) | ||
| Grade 2 | 55 (28.9%) | 9 (24.3%) | 9 (27.3%) | 8 (24.2%) | ||
| Grade 3/4 | 11 (5.8%) | 2 (5.4%) | 0.19 | 1 (3.0%) | 1 (3.0%) | 0.79 |
| Vomiting | ||||||
| All grade | 9 (4.7%) | 1 (2.7%) | 1.00 | 0 (0%) | 1 (3.0%) | 1.00 |
| Grade 1 | 8 (4.2%) | 0 (0%) | 0 (0%) | 0 (0%) | ||
| Grade 2 | 1 (0.5%) | 1 (2.7%) | 0.60 | 0 (0%) | 1 (3.0%) | 0.32 |
| Anorexia | ||||||
| All grade | 119 (62.6%) | 18 (48.7%) | 0.14 | 19 (57.6%) | 16 (48.5%) | 0.62 |
| Grade 1 | 53 (27.9%) | 6 (16.2%) | 7 (21.2%) | 6 (18.2%) | ||
| Grade 2 | 54 (28.4%) | 11 (29.7%) | 10 (30.3%) | 9 (27.3%) | ||
| Grade 3 | 12 (6.3%) | 1 (2.7%) | 0.14 | 2 (6.1%) | 1 (3.0%) | 0.45 |
| Hearing impairment | ||||||
| All grade | 3 (1.6%) | 1 (2.7%) | 0.51 | 0 (0%) | 1 (3.0%) | 1.00 |
| Grade 2 | 3 (1.6%) | 1 (2.7%) | 0.51 | 0 (0%) | 1 (3.0%) | 1.00 |
DM diabetes mellitus.
Risk factor analysis for CIN development
Multivariate logistic regression analysis in the all-patient population revealed that DM complication is a singular risk factor associated with CIN development (adjusted odds ratio; 4.31, 95% confidence interval; 1.62–11.50, P = 0.003, Table 3). Patients with NSAIDs co-administration had a higher risk of CIN, but this was not statistically significant.
Table 3.
Univariate and multivariate analyses of the risk factors associated with the incidence of CIN in all-patient population.
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Odds ratio (95%CI) | p-Value | Odds ratio (95%CI) | p-Value | |
| Sex | ||||
| Male/Female | 1.12 (0.44–2.85) | 0.82 | Excluded | – |
| Age (years) | ||||
| ≥ 65/ < 65 | 1.36 (0.57–3.24) | 0.48 | Excluded | – |
| Performance status | ||||
| 2/0 or 1 | 2.68 (0.52–13.74) | 0.24 | Excluded | – |
| Staging | ||||
| Stage IV or recurrence/others | 0.88 (0.37–2.13) | 0.78 | Excluded | – |
| Adjuvant chemotherapy | ||||
| Present/Absent | 1.12 (0.42–2.99) | 0.83 | Excluded | – |
| Radiation combination | ||||
| Present/Absent | 1.08 (0.42–2.75) | 0.88 | Excluded | – |
| Prior chemotherapy | ||||
| Present/Absent | 0.60 (0.13–2.69) | 0.50 | Excluded | – |
| BSA (m2) | ||||
| ≥ 1.5/ < 1.5 | 2.17 (0.49–9.70) | 0.31 | Excluded | – |
| Hb (g/dl) | ||||
| ≥ LLN/ < LLN | 0.95 (0.40–2.26) | 0.90 | Excluded | – |
| Alb (g/dl) | ||||
| ≥ LLN/ < LLN | 0.85 (0.36–2.01) | 0.71 | Excluded | – |
| Co-administration of PPI | ||||
| Present/Absent | 0.94 (0.39–2.23) | 0.88 | Excluded | – |
| Co-administration of NSAIDs | ||||
| Present/Absent | 2.41 (0.87–6.70) | 0.09 | 2.51 (0.85–7.43) | 0.10 |
| Cardiovascular diseases | ||||
| Present/Absent | 2.35 (0.98–5.62) | 0.06 | 1.60 (0.62–4.16) | 0.33 |
| Diabetes mellitus | ||||
| Present/Absent | 5.04 (2.01–12.63) | 0.0006** | 4.31 (1.62–11.50) | 0.003** |
**P < 0.01.
BSA body surface area, Hb hemoglobin, LLN lower limit of normal, Alb albumin, PPI proton pump inhibitor, NSAIDs non-steroidal anti-inflammatory drugs.
Discussion
DM is associated with many complications, including renal toxicity, which affects pharmacokinetics and chemotherapy toxicities25, and we sometimes administer CDDP to DM patients. Mathe et al. also reported that patients with cardiovascular diseases are at a higher risk for CIN development, and complication of DM and cardiovascular diseases further aggravates CIN19. However, they did not evaluate the aggravating action of DM alone, and an advanced CIN management strategy using magnesium supplementation was not conducted in the study. Our previous study suggested baseline DM complication as an independent risk factor for CIN development under CDDP short hydration although there was less power to evaluate the association4. This study aimed to evaluate whether CIN more frequently occurs in DM patients.
CIN incidence was significantly higher in DM complicated patients than in non-DM patients. In addition, SCr and CCr aggravation varied significantly in DM patients than in the control patients. These results were confirmed in all and propensity score-matched patient populations. Multivariate logistic regression analysis also suggested that DM complication is a singular risk factor for CIN, although cardiovascular diseases were not associated.
Oral hydration substitutes for intravenous hydration in the short hydration method4. Therefore, CINV control is important for sufficient oral hydration. However, the incidence and severity of CINV between the groups suggest that oral hydration may have been similar. Consequently, it was suggested that DM directly worsened CIN.
This is the first report suggesting that DM complication significantly degenerates CIN in advanced management. We should frequently monitor renal function in DM patients and administer additional hydration for early countermeasures in case of CIN incidence.
DM has been reported to accelerate kidney aging26,27, and long-term DM degenerates intrarenal arterial sclerosis28. Furthermore, CIN worsens in autophagy-deficient mice compared to controls29. We showed that celecoxib, a cyclooxygenase-2 selective NSAIDs, exhibits a nephroprotective effect against CIN by activating autophagy and suppressing oxidative stress30. These results suggest that autophagy works nephroprotective against CIN. In addition, Sakai et al. have reported that autophagic activity differs in type 1 and 2 diabetic nephropathies, and its induction is significantly suppressed in type 2 DM31. Most DM patients are diagnosed with type 223, and all patients in the present study were type 2. Consequently, we speculate that CIN is additively or synergistically worsened by DM-induced renal impairment or autophagy suppression. In contrast, aging was not associated with CIN development in this study. In general, aging reduces renal function19,26,27. However, it has been suggested that the organic cation transporter 2 (OCT2), which transports CDDP to the proximal tubule, has a critical role in CDDP accumulation32,33, and its expression level reportedly decreases with aging34. These suggest that there is compensation between renal function decline and CDDP accumulation reduction due to aging. Further studies evaluating these mechanisms are necessary for better CIN management in DM patients.
This study has some limitations. First, this study was retrospectively conducted with a relatively small population from a single institution. Second, as all DM patients in this study were type 2, and renal pathology differs between type 1 and 2 DM31, the results may vary for type 1 DM. Third, in all-patient population analysis, patients in the DM group were significantly older than the control patients. Aging is associated with glomerulosclerosis and arteriosclerosis of intrarenal vessels, causing nephron losss19. However, age was not a risk factor, and CIN was more common in DM patients, even in propensity-matched groups in this study. Evaluation of a balanced population in all-patient population analysis was desirable. Finally, it has been suggested that OCT2 has single-nucleotide polymorphisms (SNPs)35 and that the 808G > T SNP in OCT2 ameliorates CIN without alteration of disposition36. We did not assess patients' genetic backgrounds in this study so they might have affected the results.
In conclusion, our study revealed that DM complications significantly worsen CIN. Therefore, we should monitor DM patients cautiously and evaluate its mechanisms and countermeasures for appropriate CIN management.
Methods
Patients
This retrospective observational study enrolled lung cancer patients who received CDDP (≥ 75 mg/m2) from May 2014 to December 2021. We evaluated CDDP-including regimens such as CDDP (75 mg/m2, day 1) + pemetrexed (PEM, 500 mg/m2, day 1) ± bevacizumab (BV, 15 mg/kg, day 1), CDDP (80 mg/m2, day 1) + etoposide (ETP, 100 mg/m2, days 1–3) ± radiation, and CDDP (80 mg/m2, day 1) + vinorelbine (VNR, 20–25 mg/m2, days 1, 8) ± radiation.
All patients met the following baseline criteria: (1) age ≥ 20 years; (2) detailed patient information available from medical records; (3) 0 to 2 Eastern Cooperative Oncology Group performance status (ECOG-PS); (4) sufficient renal or liver function for CDDP-containing treatment induction. Patients who were previously administered CDDP, transferred hospital during the chemotherapy, could not complete the first cycle, and those who received dose reduction from treatment initiation were excluded. Patients administered immune checkpoint inhibitors were also excluded as we evaluated direct DM influence on CIN. The patients were divided into two groups: the DM group, which includes patients who required pharmacotherapy for DM treatment at baseline between May 2014 and December 2021, and the controls, who did not exhibit DM during the treatment between May 2014 and March 2021. If the patient had uncontrolled DM, they were treated by diabetologists before treatment induction.
We hypothesized that the CIN incidence would be 10% in the control group and 30% in the DM group, with a patient ratio of 5:1, according to our previous research4. To achieve 80% power with an alpha error of 5%, the required sample size was 190 subjects in the control group and 38 subjects in the DM group. Finally, 190 patients in the control group and 37 in the DM group were analyzed for eligibility.
The present study was approved by the Ethical Review Board for Life Science and Medical Research of Hokkaido University Hospital (Approval Number: 022-0107) and was carried out following the Declaration of Helsinki and the STROBE statement. However, given the retrospective nature of the study, informed consent from the subjects was waived by the Ethical Review Board for Life Science and Medical Research of Hokkaido University Hospital.
Treatment methods of prophylactic supportive care
All patients received the CDDP short hydration method, including 8 mEq of magnesium sulfate administration as described previously4. In addition, all regimens included the same antiemetic therapy according to the current guidelines24; intravenous palonosetron 0.75 mg on day 1, oral aprepitant 125 mg on day 1 and 80 mg on days 2, 3, and dexamethasone 9.9 mg infusion on day 1 and 8 mg orally on days 2–4.
Evaluation of CIN and other adverse effects
Toxicities in all subsequent treatment cycles were evaluated under the Common Terminology Criteria for Adverse Events, version 5.0, by physicians and pharmacists. Pharmacists confirmed appropriate CDDP administration, including oral hydration in each treatment cycle. Renal function was assessed based on the SCr variation measured by an enzymatic method. CCr was calculated using the Cockcroft-Gault formula. CIN was defined as grade 2 or higher SCr elevation in this study as well as our previous reports3,4. The primary endpoint of this study was the evaluation of CIN incidence between the groups. Secondary endpoints were assessment of SCr and CCr variation and CDDP-related adverse effects. Furthermore, propensity score-matching was performed to adjust the baseline factors between the two groups, and matched data were additionally analyzed to confirm the robustness of the primary analysis results.
Statistical analysis
The differences in baseline clinical characteristics between control and DM groups were assessed using Fisher’s exact probability test for categorical outcome variables and the Mann–Whitney U test for continuous parameters. Incidence of CIN was compared using Fisher's exact probability test, and differences in variation of SCr and CCr between the two groups were assessed using the Mann–Whitney U test. Assessment of adverse effects other than CIN was conducted using Fisher's exact probability test for the incidence and the Mann–Whitney U test for severity. The univariate and multivariate logistic regression analyses were used to identify the independent risk factor(s) for CIN incidence. We included the following baseline covariates: sex, age, ECOG PS, staging, adjuvant chemotherapy setting, radiation combination setting, prior chemotherapy existence, body surface area (BSA), hemoglobin, serum albumin levels, co-administration of proton pump inhibitors (PPI) and NSAIDs, complication of DM and cardiovascular diseases according to previous reports4,12–22. Variables that demonstrated potential associations with CIN incidence in univariate logistic regression analysis (P < 0.10) were considered when building the multivariable model. Propensity score-matching was performed using the following baseline variables: sex, age, ECOG PS, staging, adjuvant chemotherapy setting, prior treatment existence, BSA, baseline hemoglobin, albumin, SCr levels, NSAIDs and PPI co-administration, and cardiovascular disease complication. To reduce bias with these potential confounding factors, 1:1 matching (without replacement) in the two groups was achieved using the nearest neighbor method with a 0.20- width caliper of the standard deviation of the logit of propensity scores.
All analyses were performed using JMP version 16.2 statistical software (SAS Institute Japan, Tokyo, Japan). Differences were considered statistically significant when P-values were less than 0.05.
Ethics approval and consent to participate
All procedures performed in this study were carried out in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Ethical Review Board for Life Science and Medical Research of Hokkaido University Hospital (Approved Number: 022-0107). Given the retrospective nature of the study, informed consent from the subjects was waived by the Ethical Review Board for Life Science and Medical Research of Hokkaido University Hospital.
Supplementary Information
Author contributions
Designed the study: Y.S. and M.K. Performed the research: Y.S. and T.S. Analyzed the data: Y.S. Contributed new methods or models: Y.S. and M.K. Wrote the paper: Y.S. All authors have read and approved the manuscript.
Funding
This work was funded by JSPS KAKENHI Grant Number 22K15310.
Data availability
The datasets used and/or analyzed in the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-022-26454-x.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed in the current study are available from the corresponding author on reasonable request.